tbuckley/cabot-search huggingface dataset:
Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk
Authors: Naomi Wilcox, Martine Dumont, Anna González-Neira, Sara Carvalho, Charles Joly Beauparlant, Marco Crotti, Craig Luccarini, Penny Soucy, Stéphane Dubois, Rocio Nuñez-Torres, Guillermo Pita, Eugene J. Gardner, Joe Dennis, M. Rosario Alonso, Nuria Álvarez, Caroline Baynes, Annie Claude Collin-Deschesnes, Sylvie Desjardins, Heiko Becher, Sabine Behrens, Manjeet K. Bolla, Jose E. Castelao, Jenny Chang-Claude, Sten Cornelissen, Thilo Dörk, Christoph Engel, Manuela Gago-Dominguez, Pascal Guénel, Andreas Hadjisavvas, Eric Hahnen, Mikael Hartman, Belén Herráez, Benita Kiat-Tee Tan, Veronique Kiak Mien Tan, Su-Ming Tan, Geok Hoon Lim, Ern Yu Tan, Peh Joo Ho, Alexis Jiaying Khng, Audrey Jung, Renske Keeman, Marion Kiechle, Jingmei Li, Maria A. Loizidou, Michael Lush, Kyriaki Michailidou, Mihalis I. Panayiotidis, Xueling Sim, Soo Hwang Teo, Jonathan P. Tyrer, Lizet E. van der Kolk, Cecilia Wahlström, Qin Wang, John R. B. Perry, Javier Benitez, Marjanka K. Schmidt, Rita K. Schmutzler, Paul D. P. Pharoah, Arnaud Droit, Alison M. Dunning, Anders Kvist, Peter Devilee, Douglas F. Easton, Jacques Simard
Journal: Nature Genetics (2023)

Abstract Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance ( P &lt; 2.5 × 10 −6 ): the five known susceptibility genes ATM , BRCA1 , BRCA2 , CHEK2 and PALB2 , together with MAP3K1 . Associations were also observed for LZTR1 , ATRIP and BARD1 with P &lt; 1 × 10 −4 . Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.
How bibliometrics and school rankings reward unreliable science
Authors: Ivan Oransky, Adam Marcus, Alison Abritis
Journal: BMJ (2023)

How much is a citation worth?$3? $6? $100 000?Any of those answers is correct, according to back-of-the-envelope calculations over the past few decades. 1 -3 The spread between these numbers suggests that none of them is accurate, but it's inarguable that citations are the coin of the realm in academia.Bibliometrics and school rankings are largely based on publications and citations.Take the Times Higher Education rankings, for example, in which citations and papers count for more than a third of the total score. 4 Or the Shanghai Ranking, 60% of which is determined by publications and highly cited researchers. 5The QS Rankings count citations per faculty as a relatively low 20%. 6But the US News Best Global Universities ranking counts publication and citation related metrics as 60%.
Intrinsically disordered domain of transcription factor TCF-1 is required for T cell developmental fidelity
Authors: Naomi Goldman, Aditi Chandra, Isabelle Johnson, Matthew A. Sullivan, Abhijeet R. Patil, Ashley Vanderbeck, Atishay Jay, Yeqiao Zhou, Emily K. Ferrari, Leland Mayne, Jennifer Aguilan, Hai-Hui Xue, Robert B. Faryabi, E. John Wherry, Simone Sidoli, Ivan Maillard, Golnaz Vahedi
Journal: Nature Immunology (2023)
Impact of postnatal dexamethasone timing on preterm mortality and bronchopulmonary dysplasia: a propensity score analysis
Authors: T’ng Chang Kwok, Lisa Szatkowski, Don Sharkey
Journal: European Respiratory Journal (2023)

Postnatal dexamethasone (PND) is used in high-risk preterm infants after the first week of life to facilitate extubation and prevent bronchopulmonary dysplasia (BPD) but the optimal treatment timing remains unclear. Our objective was to explore the association between the timing of PND commencement and mortality and respiratory outcomes.This was a retrospective National Neonatal Research Database study of 84 440 premature infants born <32 weeks gestational age from 2010 to 2020 in England and Wales. Propensity score weighting analysis was used to explore the impact of PND commenced at three time-points (2-3 weeks (PND2/3), 4-5 weeks (PND4/5) and after 5 weeks (PND6+) chronological age) on the primary composite outcome of death before neonatal discharge and/or severe BPD (defined as respiratory pressure support at 36 weeks) alongside other secondary respiratory outcomes.3469 infants received PND. Compared with PND2/3, infants receiving PND6+ were more likely to die and/or develop severe BPD (OR 1.68, 95% CI 1.28-2.21), extubate at later postmenstrual age (mean difference 3.1 weeks, 95% CI 2.9-3.4 weeks), potentially require respiratory support at discharge (OR 1.34, 95% CI 1.06-1.70) but had lower mortality before discharge (OR 0.38, 95% CI 0.29-0.51). PND4/5 was not associated with severe BPD or discharge respiratory support.PND treatment after 5 weeks of age was associated with worse respiratory outcomes although residual bias cannot be excluded. A definitive clinical trial to determine the optimal PND treatment window, based on early objective measures to identify high-risk infants, is needed.
Orbitofrontal cortex control of striatum leads economic decision-making
Authors: Felicity Gore, Melissa Hernandez, Charu Ramakrishnan, Ailey K. Crow, Robert C. Malenka, Karl Deisseroth
Journal: Nature Neuroscience (2023)

Animals must continually evaluate stimuli in their environment to decide which opportunities to pursue, and in many cases these decisions can be understood in fundamentally economic terms. Although several brain regions have been individually implicated in these processes, the brain-wide mechanisms relating these regions in decision-making are unclear. Using an economic decision-making task adapted for rats, we find that neural activity in both of two connected brain regions, the ventrolateral orbitofrontal cortex (OFC) and the dorsomedial striatum (DMS), was required for economic decision-making. Relevant neural activity in both brain regions was strikingly similar, dominated by the spatial features of the decision-making process. However, the neural encoding of choice direction in OFC preceded that of DMS, and this temporal relationship was strongly correlated with choice accuracy. Furthermore, activity specifically in the OFC projection to the DMS was required for appropriate economic decision-making. These results demonstrate that choice information in the OFC is relayed to the DMS to lead accurate economic decision-making.
Brain regulation of gastric dysfunction induced by stress
Authors: Wan-Ying Dong, Xia Zhu, Hao-Di Tang, Ji-Ye Huang, Meng-Yu Zhu, Ping-Kai Cheng, Hao Wang, Xi-Yang Wang, Haitao Wang, Yu Mao, Wan Zhao, Yan Zhang, Wen-Juan Tao, Zhi Zhang
Journal: Nature Metabolism (2023)
Telomere length and immunosuppression in non-idiopathic pulmonary fibrosis interstitial lung disease
Authors: David Zhang, Ayodeji Adegunsoye, Justin M. Oldham, Julia Kozlitina, Nicole Garcia, Maria Poonawalla, Rachel Strykowski, Angela L. Linderholm, Brett Ley, Shwu-Fan Ma, Imre Noth, Mary E. Strek, Paul J. Wolters, Christine Kim Garcia, Chad A. Newton
Journal: European Respiratory Journal (2023)

Background Studies suggest a harmful pharmacogenomic interaction exists between short leukocyte telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD). Methods A retrospective, multicentre cohort analysis was performed in fibrotic hypersensitivity pneumonitis (fHP), unclassifiable ILD (uILD) and connective tissue disease (CTD)-ILD patients from five centres. LTL was measured by quantitative PCR for discovery and replication cohorts and expressed as age-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL on 2-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure. Results The discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of patients were exposed to immunosuppression and 22% had LTL &lt;10th percentile of normal. fHP and uILD patients with LTL &lt;10th percentile experienced reduced survival when exposed to either mycophenolate or azathioprine in the discovery cohort (mortality hazard ratio (HR) 4.97, 95% CI 2.26–10.92; p&lt;0.001) and replication cohort (mortality HR 4.90, 95% CI 1.74–13.77; p=0.003). Immunosuppressant exposure was not associated with differential survival in patients with LTL ≥10th percentile. There was a significant interaction between LTL &lt;10th percentile and immunosuppressant exposure (discovery p interaction =0.013; replication p interaction =0.011). Low event rate and prevalence of LTL &lt;10th percentile precluded subgroup analyses for CTD-ILD. Conclusion Similar to IPF, fHP and uILD patients with age-adjusted LTL &lt;10th percentile may experience reduced survival when exposed to immunosuppression.
Progress Toward Poliomyelitis Eradication — Pakistan, January 2022–June 2023
Authors: Chukwuma Mbaeyi, Shahzad Baig, Rana Muhammad Safdar, Zainul Khan, Hamish Young, Jaume Jorba, Zubair M. Wadood, Hamid Jafari, Muhammad Masroor Alam, Richard Franka
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Since the establishment of the Global Polio Eradication Initiative in 1988, Pakistan remains one of only two countries (along with Afghanistan) with continued endemic transmission of wild poliovirus (WPV). This report describes Pakistan's progress toward polio eradication during January 2022-June 2023. During 2022, Pakistan reported 20 WPV type 1 (WPV1) cases, all of which occurred within a small geographic area encompassing three districts in south Khyber Pakhtunkhwa. As of June 23, only a single WPV1 case from Bannu district in Khyber Pakhtunkhwa province has been reported in 2023, compared with 13 cases during the same period in 2022. In addition, 11 WPV1 isolates have been reported from various environmental surveillance (ES) sewage sampling sites to date in 2023, including in Karachi, the capital of the southern province of Sindh. Substantial gaps remain in the quality of supplementary immunization activities (SIAs), especially in poliovirus reservoir areas. Despite the attenuation and apparently limited geographic scope of poliovirus circulation in Pakistan, the isolation of WPV1 from an ES site in Karachi is cause for concern about the actual geographic limits of transmission. Interrupting WPV1 transmission will require meticulous tracking and sustained innovative efforts to vaccinate children who are regularly missed during SIAs and rapidly responding to any new WPV1 isolations.
<i>Notes from the Field:</i> Outbreak of Norovirus Linked to a Food Establishment — Illinois, November 2022
Authors: Megan N. Hanley, Shana M. Altman, Angie Phillips
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

On November 26, 2022, the Tazewell (Illinois) County Health Department (TCHD) contacted the Illinois Department of Public Health (IDPH) concerning a large acute gastroenteritis outbreak linked to restaurant A in Illinois.TCHD conducted an outbreak investigation with the assistance of IDPH, including a case-control study that identified 317 norovirus infections among respondents (excluding the primary patient) who dined at restaurant A during November 19-26, 2022.
Newly diagnosed and relapsed epithelial ovarian cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
Authors: A. González-Martín, P. Harter, A. Leary, D. Lorusso, R.E. Miller, B. Pothuri, I. Ray-Coquard, D.S.P. Tan, E. Bellet, A. Oaknin, J.A. Ledermann
Journal: Annals of Oncology (2023)
P833: MARCH5 AS A POTENTIAL THERAPEUTIC TARGET IN MULTIPLE MYELOMA
Authors: Hamed Bashiri, Ahad Khalilnezhad, Haruhito Totani, Chung Tae-Hoon, Wee Joo Chng, Joe Yeong, Toshio Suda
Journal: HemaSphere (2023)

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: MARCH5 (Membrane Associated Ring-CH-Type Finger 5, also known as MITOL) is an E3 ubiquitin ligase localized on the outer membrane of mitochondria which plays a crucial role in controlling mitochondrial dynamics. A close link between disturbed mitochondrial dynamics and cancers has been demonstrated. Also, MARCH5 RNA may act as a competing endogenous RNA in the expression regulation of SMAD2 and ATG5, leading to an enhanced autophagic activity. MARCH5 is indicated to be an essential gene in different multiple myeloma (MM) cell lines which produce aberrant immunoglobulin. Therefore, we hypothesize that it may play an oncogenic role in MM malignancy. Aims: To elucidate the biological functions and clinical significance of MARCH5 in MM and the underlying mechanisms. Methods: The effects of MARCH5 depletion on cell biology were determined through lentiviral knockdown of MARCH5 in several MM cell lines including KMS11, KMS18, RPMI8226 and MM.1s, and subsequent in vitro assays such as cell viability, growth, and apoptosis analysis. The mechanisms behind MARCH5 regulation of MM cell viability and apoptosis were evaluated by qPCR, Western blot (WB), Cyto ID staining and RNA sequencing techniques. In addition, clinical importance of MARCH5 was explored in various datasets including HOVON and CoMMpass datasets as well as Italian and Singaporean (CWJ) groups. Results: Cell viability and cell growth of MM cell lines were significantly decreased associated with a significant increase in apoptosis upon MARCH5 depletion, mainly due to the reduced autophagic activity, as demonstrated by a downregulation of LC3I/II along with BECLIN1, the key proteins in the autophagosome initiation and formation. Consistent to WB and RNA seq results, Cyto ID staining analysis showed a reduced autophagosome formation in knockdown groups vs Scramble, further confirming the reduced autophagic activity. Furthermore, a downregulation of IRE1 and XBP1s, mediators of signals enhancing protein folding and degradation of un-/mis-folded proteins, was observed which might explain the aggravated compromised cell survival. Moreover, patient sample-derived RNA-seq and tissue microarray data analysis revealed that MARCH5 expression was progressively increased during the course of MM malignancy and has a strong correlation with overall survival (OS) and progression free survival (PFS), indicating a possible oncogenic role of MARCH5 in MM disease formation and progression. Summary/Conclusion: Collectively, our findings indicate that MARCH5 may play a crucial oncogenic role in MM cells. Regarding the clinical data base, MARCH5 correlation with MM disease progression as well as OS and PFS may provide evidence on the therapeutic targeting of MARCH5 for MM therapy. Keywords: Multiple myeloma
Non-canonical STING–PERK pathway dependent epigenetic regulation of vascular endothelial dysfunction via integrating IRF3 and NF-κB in inflammatory response
Authors: Xuesong Li, Xiang Chen, Longbin Zheng, Minghong Chen, Yunjia Zhang, Ruigong Zhu, Jiajing Chen, Jiaming Gu, Quanwen Yin, Hong Jiang, Xuan Wu, Xian Ji, Xin Tang, Mengdie Dong, Qingguo Li, Yuanqing Gao, Hongshan Chen
Journal: Acta Pharmaceutica Sinica B (2023)

Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis, while the underlying mechanism remains elusive. Here, we report that the non-canonical stimulator of interferon genes (STING)-PKR-like ER kinase (PERK) pathway was significantly activated in both human and mice atherosclerotic arteries. Typically, STING activation leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB)/p65, thereby facilitating IFN signals and inflammation. In contrast, our study reveals the activated non-canonical STING-PERK pathway increases scaffold protein bromodomain protein 4 (BRD4) expression, which encourages the formation of super-enhancers on the proximal promoter regions of the proinflammatory cytokines, thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF-κB via a condensation process. Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation. Mechanistically, this pathway is triggered by leaked mitochondrial DNA (mtDNA) via mitochondrial permeability transition pore (mPTP), formed by voltage-dependent anion channel 1 (VDAC1) oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation. Especially, compared to macrophages, endothelial STING activation plays a more pronounced role in atherosclerosis. We propose a non-canonical STING-PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3, NF-κB and BRD4 in inflammatory responses, which provides emerging therapeutic modalities for vascular endothelial dysfunction.
Long-acting microneedle formulations
Authors: Lalitkumar K. Vora, Akmal H. Sabri, Yara Naser, Achmad Himawan, Aaron R.J. Hutton, Qonita Kurnia Anjani, Fabiana Volpe-Zanutto, Deepakkumar Mishra, Mingshan Li, Aoife M. Rodgers, Alejandro J. Paredes, Eneko Larrañeta, Raghu Raj Singh Thakur, Ryan F. Donnelly
Journal: Advanced Drug Delivery Reviews (2023)

The minimally-invasive and painless nature of microneedle (MN) application has enabled the technology to obviate many issues with injectable drug delivery. MNs not only administer therapeutics directly into the dermal and ocular space, but they can also control the release profile of the active compound over a desired period. To enable prolonged delivery of payloads, various MN types have been proposed and evaluated, including dissolving MNs, polymeric MNs loaded or coated with nanoparticles, fast-separable MNs hollow MNs, and hydrogel MNs. These intricate yet intelligent delivery platforms provide an attractive approach to decrease side effects and administration frequency, thus offer the potential to increase patient compliance. In this review, MN formulations that are loaded with various therapeutics for long-acting delivery to address the clinical needs of a myriad of diseases are discussed. We also highlight the design aspects, such as polymer selection and MN geometry, in addition to computational and mathematical modeling of MNs that are necessary to help streamline and develop MNs with high translational value and clinical impact. Finally, up-scale manufacturing and regulatory hurdles along with potential avenues that require further research to bring MN technology to the market are carefully considered. It is hoped that this review will provide insight to formulators and clinicians that the judicious selection of materials in tandem with refined design may offer an elegant approach to achieve sustained delivery of payloads through the simple and painless application of a MN patch.
Bringing it all together: Wearable data fusion
Authors: Yunus Celik, Alan Godfrey
Journal: npj Digital Medicine (2023)

Contemporary wearables like smartwatches are often equipped with advanced sensors and have associated algorithms to aid researchers monitor physiological outcomes like physical activity levels, sleep patterns or heart rate in free-living environments. But here’s the catch: all that valuable data is often collected separately because the sensors don’t always play nice with each other, and it’s a real challenge to put all the data together. To get the full picture, we may often need to combine different data streams. It’s like putting together a puzzle of our health, instead of just looking at individual pieces. This way, we can gather more useful info and better understand health (it’s called digital twinning). Yet, to do so requires robust sensor/data fusion methods at the signal, feature, and decision levels. Selecting the appropriate techniques based on the desired outcome is crucial for successful implementation. An effective data fusion framework along with the right sensor selection could contribute to a more holistic approach to health monitoring that extends beyond clinical settings.
Spatial transcriptomics: recent developments and insights in respiratory research
Authors: Wen-Jia Wang, Liu-Xi Chu, Li-Yong He, Ming-Jing Zhang, Kai-Tong Dang, Chen Gao, Qin-Yu Ge, Zhou-Guang Wang, Xiang-Wei Zhao
Journal: Military Medical Research (2023)

Abstract The respiratory system’s complex cellular heterogeneity presents unique challenges to researchers in this field. Although bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) have provided insights into cell types and heterogeneity in the respiratory system, the relevant specific spatial localization and cellular interactions have not been clearly elucidated. Spatial transcriptomics (ST) has filled this gap and has been widely used in respiratory studies. This review focuses on the latest iterative technology of ST in recent years, summarizing how ST can be applied to the physiological and pathological processes of the respiratory system, with emphasis on the lungs. Finally, the current challenges and potential development directions are proposed, including high-throughput full-length transcriptome, integration of multi-omics, temporal and spatial omics, bioinformatics analysis, etc. These viewpoints are expected to advance the study of systematic mechanisms, including respiratory studies.
S1P-S1PR3-RAS promotes the progression of S1PR3hi TAL1+ T-cell acute lymphoblastic leukemia that can be effectively inhibited by an S1PR3 antagonist
Authors: Dan Zhu, Tingting Jiang, Deyu Ma, Hongyang Zhang, Jia Zhang, Wenqiong Lv, Maoyuan Gong, Haobiao Wang, Ziyang Liu, Hongyu Su, Lamei Zeng, Shan Liu, Shi Tang, Bijie Yang, Filippus I. Tshavuka, Guo Fu, Zidai Liu, Danyi Peng, Haiyan Liu, Zijun Yan, Ziyang Cao, Hui Zhao, Tong-Chuan He, Jie Yu, Yi Shu, Lin Zou
Journal: Leukemia (2023)